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This version published online on February 7, 2006
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-2610
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Submitted on December 1, 2005
Accepted on January 26, 2006

Smaller left anterior cingulate cortex volumes are associated with impaired hypothalamic-pituitary-adrenal axis regulation in healthy elderly men

Alasdair MJ MacLullich*, Karen J Ferguson, Joanna M Wardlaw, John M Starr, Ian J Deary, and Jonathan R Seckl

Endocrinology Unit, Centre for Cardiovascular Science, University of Edinburgh, Queen's Medical Research Institute, 47 Little France Crescent, Edinburgh, EH16 4TJ.; Division of Clinical Neurosciences, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, UK.; Royal Victoria Hospital, Craigleith Road, Edinburgh, Edinburgh EH4 2DN, UK; Department of Psychology, University of Edinburgh, 7 George Square, Edinburgh EH8 9JZ, UK

* To whom correspondence should be addressed. E-mail: a.maclullich{at}ed.ac.uk.

Context: Studies in animals suggest that the limbic prefrontal cortex, including anterior cingulate cortex, is involved in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, but human data are lacking.

Objective: This study tested the hypothesis that smaller anterior cingulate cortex volumes are associated with HPA axis dysregulation in healthy older men.

Design and participants: Comparison of volumes of bilateral anterior cingulate cortex, hippocampus and superior frontal gyrus (control region) volumes in two groups of 10 healthy men aged 65-70 who showed non-suppression or suppression of cortisol levels to low dose (250mcg) dexamethasone. Analysis of brain volumes was performed blind to the cortisol levels.

Setting: Tertiary care clinical research center.

Results: Non-suppressors had significantly smaller left anterior cingulate cortex volumes than suppressors (5757 mm2 vs. 7817 mm2; P = 0.01). Right anterior cingulate cortex, bilateral hippocampus and bilateral superior frontal gyrus volumes were not significantly different between non-suppressors and suppressors.

Conclusions: Smaller left anterior cingulate cortex volumes may be associated with HPA axis dysregulation in humans. These results substantiate evidence from animal studies indicating an important role for the anterior cingulate cortex in suprahypothalamic feedback regulation of the HPA axis. The results also have implications for disorders in which HPA axis dysregulation and abnormalities of the anterior cingulate cortex are frequently observed, such as depression and Alzheimer's disease.
Key words: anterior cingulate cortex • medial prefrontal cortex • hippocampus • glucocorticoids • hypothalamic-pituitary-adrenal axis • ageing • cortisol




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